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Molecular and Cellular Biology

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https://www.readbyqxmd.com/read/28193847/dna-damage-response-independent-role-for-mdc1-in-maintaining-genomic-stability
#1
Zhiguo Li, Chen Shao, Yifan Kong, Colin Carlock, Nihal Ahmad, Xiaoqi Liu
MDC1 is a central player in checkpoint activation and subsequent DNA repair following DNA damage. Although MDC1 has been extensively studied, much of its known functions to date pertains to the DNA damage response (DDR) pathway. Herein, we report a novel function of phosphorylated MDC1, independent of ATM and DNA damage, which is required for proper mitotic progression and maintenance of genomic stability. We demonstrate that MDC1 is an in vivo target of Plk1 and that the phosphorylated MDC1 is dynamically localized to nuclear envelopes, centrosomes, kinetochores and the midbodies...
February 13, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28193846/protein-4-1r-exon-16-3-splice-site-activation-requires-coordination-among-tia1-pcbp1-and-rbm39-during-terminal-erythropoiesis
#2
Shu-Ching Huang, Henry S Zhang, Brian Yu, Ellen McMahon, Dan T Nguyen, Faye H Yu, Alexander C Ou, Jennie Park Ou, Edward J Benz
Exon 16 of protein 4.1R encodes a spectrin/actin-binding peptide critical for erythrocyte membrane stability. Its expression during erythroid differentiation is regulated by alternative pre-mRNA splicing. A UUUUCCCCCC-motif situated between the branch point and the 3' splice site is crucial for inclusion. We show that the "UUUU" region and the last 3 C's in this motif are necessary for the binding of splicing factors TIA1 and Pcbp1, and that these proteins appear to act in a collaborative manner to enhance exon 16 inclusion...
February 13, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28193845/the-predicted-rna-binding-proteins-pes4-and-mip6-regulate-mrna-levels-translation-and-localization-during-sporulation-in-budding-yeast
#3
Liang Jin, Kai Zhang, Rolf Sternglanz, Aaron M Neiman
In response to starvation, diploid cells of Saccharomyces cerevisiae undergo meiosis and form haploid spores, a process collectively referred to as sporulation. The differentiation into spores requires extensive changes in gene expression. The transcriptional activator Ndt80 is a central regulator of this process, which controls many genes essential for sporulation. Ndt80 induces ∼300 genes coordinately during meiotic prophase, but different mRNAs within the NDT80-regulon are translated at different times during sporulation...
February 13, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28167607/a-key-regulator-of-cell-adhesion-identification-and-characterization-of-important-n-glycosylation-sites-on-integrin-%C3%AE-5-for-cell-migration
#4
Qinglei Hang, Tomoya Isaji, Sicong Hou, Yuqin Wang, Tomohiko Fukuda, Jianguo Gu
The N-glycosylation of integrin α5β1 is thought to control many fundamental aspects of cell behavior, including cell adhesion and migration. However, the mechanism of how N-glycans function remains largely obscure. Here, we used a loss-of-function approach. The wild-type (WT) and N-glycosylation mutant integrin α5, S3-5 (sites 3, 4 and 5), which contains fewer N-glycans, were stably reconstituted in α5-knock-out cancer cells. We found that the migration ability of the S3-5 cells was decreased by comparison with the WT...
February 6, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28167606/the-deubiquitinating-enzyme-usp20-regulates-erk3-stability-and-biological-activity
#5
Simon Mathien, Paul Déléris, Mathilde Soulez, Laure Voisin, Sylvain Meloche
Extracellular signal-regulated kinase 3 (ERK3) is an atypical mitogen-activated protein (MAP) kinase whose regulatory mechanisms and biological functions remain superficially understood. Contrary to most protein kinases, ERK3 is a highly unstable protein that is subject to dynamic regulation by the ubiquitin-proteasome system. However, the effectors that control ERK3 ubiquitination and degradation are unknown. In this study, we carried out an unbiased functional loss-of-function screen of the human deubiquitinating enzyme (DUB) family and identified ubiquitin-specific protease 20 (USP20) as a novel ERK3 regulator...
February 6, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28167605/thymus-derived-treg-cell-development-is-regulated-by-c-type-lectin-mediated-bic-mirna155-expression
#6
Raquel Sánchez-Díaz, Rafael Blanco-Dominguez, Sandra Lasarte, Katerina Tsilingiri, Enrique Martín-Gayo, Beatriz Linillos-Pradillo, Hortensia de la Fuente, Francisco Sánchez-Madrid, Rinako Nakagawa, María L Toribio, Pilar Martín
Thymus-derived regulatory T cells (tTregs) are key to prevent autoimmune diseases but the mechanisms involved in their development remain unsolved. Here, we show that the C-type lectin receptor CD69 controls tTreg cell development and peripheral Treg homeostasis through the regulation of BIC/miR-155 and its target, the suppressor of cytokine signaling 1 (SOCS-1). Using Foxp3-mRFP/cd69(+/-) or/cd69(-/-) reporter mice, shRNA-mediated silencing and miR-155 transfection approaches, we found that CD69 deficiency impaired the signal transducer and activator of transcription 5 (STAT5) pathway in Foxp3(+) cells...
February 6, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28167604/gs-dreadd-knock-in-mice-for-tissue-specific-temporal-stimulation-of-camp-signaling
#7
Dmitry Akhmedov, Maria G Mendoza-Rodriguez, Kavitha Rajendran, Mario Rossi, Jürgen Wess, Rebecca Berdeaux
Hundreds of hormones and ligands stimulate cAMP signaling in different tissues through activation of G protein-coupled receptors (GPCRs). Although functions and individual effectors of cAMP signaling are well characterized in many tissues, pleiotropic effects of GPCR agonists limit investigation of physiologic functions of cAMP signaling in individual cell types at different developmental stages in vivo To facilitate studies of cAMP signaling in specific cell populations in vivo, we harnessed the power of DREADD (Designer Receptors Exclusively Activated by Designer Drugs) technology by creating ROSA26-based knock-in mice for conditional expression of a Gs-coupled DREADD (rM3Ds-GFP, or "GsD")...
February 6, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28137913/chromatin-domain-organization-of-tcrb-locus-and-its-perturbation-by-ectopic-ctcf-binding
#8
Pratishtha Rawat, Manisha Jalan, Ananya Sadhu, Abhilasha Kanaujia, Madhulika Srivastava
CTCF mediated chromatin interactions influence organization and function of mammalian genome in diverse ways. We analyzed the interactions amongst CTCF binding sites (CBS) at murine TCRb locus to discern the role of CTCF mediated interactions in regulation of transcription and VDJ recombination. 3C analysis revealed thymocyte specific long-range intrachromosomal interactions amongst various CBS across the locus that were relevant for defining the limit of enhancer Eb regulated Recombination Centre (RC) and for facilitating the spatial proximity of Trbv segments to RC...
January 30, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28137912/l2hgdh-deficiency-accumulates-l-2-hydroxyglutarate-with-progressive-leukoencephalopathy-and-neurodegeneration
#9
Shenghong Ma, Renqiang Sun, Bowen Jiang, Jun Gao, Wanglong Deng, Peng Liu, Ruoyu He, Jing Cui, Minbiao Ji, Wei Yi, Pengyuan Yang, Xiaohui Wu, Yue Xiong, Zilong Qiu, Dan Ye, Kun-Liang Guan
L-2-hydroxyglutarate aciduria (L-2-HGA) is an autosomal recessive neurometabolic disorder caused by a mutation in the L-2-hydroxyglutarate dehydrogenase (L2HGDH) gene. In this study, we generated L2hgdh knockout (KO) mice and observed a robust increase of 2-hydroxyglutarate (L-2-HG) levels in multiple tissues. The highest levels of L-2-HG were observed in the brain and testis with a corresponding increase in histone methylation in these tissues. L2hgdh KO mice exhibit white matter abnormalities, extensive gliosis, microglia-mediated neuroinflammation, and an expansion of oligodendrocyte progenitor cells (OPCs)...
January 30, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28137911/the-effects-of-mutations-on-the-aggregation-propensity-of-the-human-prion-like-protein-hnrnpa2b1
#10
Kacy R Paul, Amandine Molliex, Sean Cascarina, Amy E Boncella, J Paul Taylor, Eric D Ross
Hundreds of human proteins contain prion-like domains, which are a subset of low-complexity domains with high amino acid compositional similarity to yeast prion domains. A recently characterized mutation in the prion-like domain of the human heterogeneous nuclear ribonucleoprotein hnRNPA2B1 increases the aggregation propensity of the protein, and causes multisystem proteinopathy. The mutant protein forms cytoplasmic inclusions when expressed in Drosophila; the mutation accelerates aggregation in vitro; and the mutant prion-like domain can substitute for a portion of a yeast prion domain in supporting prion activity...
January 30, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28137910/osteogenesis-is-improved-by-low-tumour-necrosis-factor-%C3%AE-concentration-through-the-modulation-of-gs-coupled-receptor-signals
#11
Simona Daniele, Letizia Natali, Chiara Giacomelli, Pietro Campiglia, Ettore Novellino, Claudia Martini, Maria Letizia Trincavelli
In the early phase of bone damage, low concentrations of the cytokine Tumour Necrosis factor-alpha (TNF-α) favour osteoblast differentiation. In contrast, chronic high doses of the same cytokine contribute to bone loss, demonstrating opposite effects in dependence on its concentration and on the time of exposure.In the bone microenvironment, TNF-α modulates the expression/function of different G protein coupled receptors (GPCRs) and of their regulatory proteins, GPCR regulated kinases (GRKs), thus dictating their final biological outcome in controlling bone anabolic processes...
January 30, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28137909/ndr1-dependent-regulation-of-kindlin-3-controls-high-affinity-lfa-1-binding-and-immune-synapse-organization
#12
Naoyuki Kondo, Yoshihiro Ueda, Toshiyuki Kita, Madoka Ozawa, Takashi Tomiyama, Kaneki Yasuda, Dae-Sik Lim, Tatsuo Kinashi
Antigen-specific adhesion between T cells and antigen-presenting cells (APC) during the formation of the immunological synapse (IS) is mediated by LFA-1 and ICAM-1. Herein, LFA-1/ICAM-1 interactions were measured at the single-molecule level on supported lipid bilayers. High-affinity binding was detected at low frequencies in the inner peripheral supramolecular activation cluster (SMAC) zone that contained high levels of activated Rap1 and kindlin-3. Rap1 was essential for T cell attachment, whereas deficiencies of ste20-like kinases, Mst1/Mst2 diminished high-affinity binding, and abrogated central SMAC formation with mislocalized kindlin-3 and vesicle transport regulators involved in TCR recycling/releasing machineries, resulting in impaired T-APC interactions...
January 30, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28137908/the-pp2a-b56-phosphatase-opposes-cyclin-e-autocatalytic-degradation-via-site-specific-dephosphorylation
#13
Ryan J Davis, Jherek Swanger, Bridget T Hughes, Bruce E Clurman
Cyclin E, in conjunction with its catalytic partner cyclin-dependent kinase 2 (CDK2), regulates cell cycle progression as cells exit quiescence and enter S-phase. Multiple mechanisms control cyclin E periodicity during the cell cycle, including phosphorylation-dependent cyclin E ubiquitylation by the SCF(Fbw7) ubiquitin ligase. Serine 384 (S384) is the critical cyclin E phosphorylation site that stimulates Fbw7 binding and cyclin E ubiquitylation and degradation. Because S384 is autophosphorylated by bound CDK2, this presents a paradox as to how cyclin E can evade autocatalytically induced degradation in order to phosphorylate its other substrates...
January 30, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28115426/p97-negatively-regulates-nrf2-by-extracting-ubiquitylated-nrf2-from-the-keap1-cul3-e3-complex
#14
Shasha Tao, Pengfei Liu, Gang Luo, Montserrat Rojo de la Vega, Heping Chen, Tongde Wu, Joseph Tillotson, Eli Chapman, Donna D Zhang
Activation of the stress responsive transcription factor NRF2 is the major line of defense to combat oxidative or electrophilic insults. Under basal conditions, NRF2 is continuously ubiquitylated by the KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex and targeted to the proteasome for degradation (the canonical mechanism). However, the path from the CUL3 complex to ultimate proteasomal degradation had been previously unknown. p97 is an ubiquitin-targeted ATP-dependent segregase that extracts ubiquitylated client proteins from membranes, protein complexes, or chromatin and has an essential role in autophagy and the ubiquitin proteasome system (UPS)...
January 23, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28096188/erk1-2-phosphorylate-gab2-to-promote-a-negative-feedback-loop-that-attenuates-pi3k-akt-signaling
#15
Xiaocui Zhang, Geneviève Lavoie, Antoine Méant, Léo Aubert, Marie Cargnello, André Haman, Trang Hoang, Philippe P Roux
The scaffolding adapter protein Gab2 (Grb2-associated binder) promotes cell proliferation, survival and motility by engaging several signaling pathways downstream of growth factor and cytokine receptors. In particular, Gab2 plays essential roles in mast cells as it is required for PI3K (phosphoinositide 3-kinase) activation in response to Kit and the high-affinity IgE receptor. While the positive role of Gab2 in PI3K signaling is well documented, very little is known about the mechanisms that attenuate its function...
January 17, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28069743/derepression-of-the-dna-methylation-machinery-of-gata1-gene-triggers-the-differentiation-cue-for-erythropoiesis
#16
Lei Yu, Jun Takai, Akihito Otsuki, Fumiki Katsuoka, Mikiko Suzuki, Saori Katayama, Masahiro Nezu, James Douglas Engel, Takashi Moriguchi, Masayuki Yamamoto
GATA1 is a critical regulator of erythropoiesis. While the mechanisms underlying the high-level expression of GATA1 in maturing erythroid cells have been studied extensively, the initial activation of the Gata1 gene in early hematopoietic progenitors remains to be elucidated. We previously identified a hematopoietic stem and progenitor cell (HSPC)-specific silencer element (the Gata1 methylation determining region; G1MDR) that recruits DNA methyltransferase 1 (Dnmt1) and provokes the methylation of the Gata1 gene enhancer...
January 9, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28069742/islet1-dependent-%C3%AE-catenin-hedgehog-signaling-is-required-for-outgrowth-of-the-lower-jaw
#17
Feixue Li, Guoquan Fu, Ying Liu, Xiaoping Miao, Yan Li, Xueqin Yang, Xiaoyun Zhang, Dongliang Yu, Lin Gan, Mengsheng Qiu, Yiping Chen, Ze Zhang, Zunyi Zhang
Mandibular patterning information initially resides in the epithelium during development. However, how transcriptional regulation of epithelial-derived signaling controls morphogenesis of the mandible remains elusive. Using Shh(Cre) to target the mandibular epithelium, we ablated transcription factor Islet1, resulting in a distally truncated mandible via unbalanced cell apoptosis and decreased cell proliferation in the distal mesenchyme. Loss of Islet1 caused a lack of cartilage at the distal tip, leading to the two growing mandibular elements to be fused surrounding the rostral process of Meckels cartilage...
January 9, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28069741/tor-complex-2-regulated-protein-kinase-fpk1-stimulates-endocytosis-via-inhibition-of-ark1-prk1-related-protein-kinase-akl1-in-saccharomyces-cerevisiae
#18
Françoise M Roelants, Kristin L Leskoske, Ross T A Pedersen, Alexander Muir, Jeffrey M-H Liu, Gregory C Finnigan, Jeremy Thorner
Depending on the stress, plasma membrane alterations activate or inhibit yeast Target of Rapamycin (TOR) Complex 2, which, in turn, upregulates or downregulates the activity of its essential downstream effector, protein kinase Ypk1. Through phosphorylation of multiple substrates, Ypk1 controls many processes that restore homeostasis. One such substrate is protein kinase Fpk1, which is negatively regulated by Ypk1. Fpk1 phosphorylates and stimulates flippases that translocate aminoglycerophospholipids from the outer to the inner leaflet of the plasma membrane...
January 9, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28069740/checkpoint-independent-regulation-of-origin-firing-by-mrc1-through-interaction-with-hsk1-kinase
#19
Seiji Matsumoto, Yutaka Kanoh, Michie Shimmoto, Motoshi Hayano, Kyosuke Ueda, Rino Fukatsu, Naoko Kakusho, Hisao Masai
Mrc1 is a conserved checkpoint mediator protein that transduces replication-stress signal to downstream effector kinase. Loss of mrc1 checkpoint activity results in aberrant activation of late/dormant origins in the presence of hydroxyurea. Mrc1 was also suggested to regulate orders of early-origin firing in a checkpoint-independent manner, but its mechanism was unknown. Here we identify HBS (Hsk1 Bypass Segment) on Mrc1. ΔHBS does not suppress late/dormant origin firing in the presence of hydroxyurea but causes precocious and enhanced activation of weak early-firing origins during normal S-phase progression, and bypasses the requirement of Hsk1 for growth...
January 9, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28069739/a-two-tiered-mechanism-enables-localized-cdc42-signaling-during-enterocyte-polarization
#20
Lucas J M Bruurs, Susan Zwakenberg, Mirjam C van der Net, Fried J Zwartkruis, Johannes L Bos
Signaling by the small GTPase Cdc42 governs a diverse set of cellular processes that contribute to tissue morphogenesis. Since these processes often require highly localized signaling, Cdc42 activity must be clustered in order to prevent ectopic signaling. During cell polarization, apical Cdc42 signaling directs the positioning of the nascent apical membrane. However, the molecular mechanisms that drive Cdc42 clustering during polarity establishment are largely unknown.Here we demonstrate that during cell polarization localized Cdc42 signaling is enabled via activity-dependent control of Cdc42 mobility...
January 9, 2017: Molecular and Cellular Biology
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